The project focuses on the role of TNFR1 and IKKa in the development of lung squamous cell carcinoma and metastasis. Lung Cancer is the leading cause of cancer mortality worldwide and its pathogenesis is highly associated with pulmonary inflammation. Although TNF/TNFR1 is frequently described as a major inflammatory signaling in human lung cancers, the mechanism underlying the proceeding of cancer cell biology and its therapeutic potential remain unknown. Previously, we demonstrated that kinase-dead IKKa knockin (L-IkkaKA/KA) mice develop spontaneous lung SCCs, which was published in Cancer Cell 2013. Recently, we detected the overexpressed TNFR1 levels in a proportion of human lung squamous cell carcinoma (SCC) and in mouse spontaneous lung SCCs derived from L-IkkaKA/KA mice. Our results showed that the excess TNFR1 levels led well-differentiated SCC to spindle cell carcinoma (a final stage of SCCs) and metastasis, characterized by a combined cellular property of stemness, dedifferentiation, and epithelial-mesenchymal transition (EMT). The increased TNFR1/TNF autocrine and paracrine signalings triggered the activities of transcription factors Brd4 and c-Rel NF-kB to upregulate the expression of Ubch10 that encodes an oncogenic E2 conjugated enzyme, consequently enhancing the levels of the regulators of stem cells, EMT, cell survival, and dedifferentiation. Knocking-down TNFR1 or the transcription factors and/or reintroducing IKKa inhibited the development of tumors and metastasis. Consistently, isolated human lung stem-like SCC cells expressed increased TNFR1 levels and developed lung SCCs and metastasis. Furthermore, deleting TNFR1 prevented lung SCC development in mice. This study advances a concept of the integrated proceeding of inflammatory signaling, cancer stem cell, dedifferentiation, and EMT in the pathogenesis of aggressive lung SCC and metastasis, and provides potential targets for interventional and precise treatment of human lung SCCs. We already generated transgenic K5-TNFR1 mice that specifically overexpress TNFR1 in the squamous epithelial cells and further generated L-IkkaKA/KA K5.TNFR1 mice. We will determine whether overexpressed TNFR1 promotes lung SCC development in the mice.